Associations of fecal immunochemical test positivity with risks of cancer incidence and mortality: findings from a community-based screening program in Pudong New Area of Shanghai, China

Background Fecal immunochemical test (FIT) has been widely used for colorectal cancer (CRC) screening. Studies suggested that FIT positivity could predict cancer risk beyond colorectal cancer. This study evaluated the associations of FIT results with site-specific cancer incidence and mortality across 17 cancer sites in a large community-based cohort. Methods This prospective cohort included 427, 560 residents aged 50–74 years who participated in the Shanghai Pudong New Area CRC screening program (2013-2019), and followed until December 31, 2021. Participants were classified based on the results of two consecutive FITs: negative (n=374, 633), single-positive (n=42, 269), and double-positive (n=10, 658). Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for site-specific cancer incidence and mortality, with adjustment for sociodemographic and lifestyle factors. Results During a mean follow-up of 6.7 years, double-positive FIT was associated with a markedly elevated risk of CRC incidence (HR = 8.49, 95% CI: 7.67-9.39) and mortality (HR = 8.27, 95% CI: 6.59-10.38), with a clear gradient ( P trend < 0.001); among FIT-positive participants, double-positive FIT conferred higher CRC risk than single-positive FIT (incidence HR = 3.15, 95% CI: 2.80-3.56; mortality HR = 3.93, 95% CI: 2.95-5.23). Within the first 2 years after screening, double-positive FIT was associated with CRC incidence (HR = 26.15, 95% CI: 22.58-30.29) and mortality (HR = 9.63, 95% CI: 4.31-21.51); in landmark analyses beginning 2 years after FIT assessment, double-positive FIT remained associated with CRC incidence (HR = 3.47, 95% CI: 2.94-4.11) and mortality (HR = 5.01, 95% CI: 3.60-6.97), indicating not only screening-detected prevalent cancer but also future risk. FIT positivity was also associated with increased risk of upper gastrointestinal cancer incidence (double-positive HR = 1.56, 95% CI: 1.27-1.93) and mortality (single-positive HR = 1.37, 95% CI: 1.14-1.63), with significant linear trends ( P trend < 0.001). In contrast, no significant associations were observed for other cancer sites. Conclusions In this large cohort, FIT positivity showed a strong association with CRC risk, with a clear gradient across single-positive and double-positive groups, a moderate association with upper GI cancer risk, and no significant association with other cancer sites. These findings support colonoscopy for FIT-positive individuals, especially double-positive, and warrant evaluation of whether selective upper gastrointestinal assessment may be beneficial.